Proposed is a collaborative partnership between Makerere University and Johns Hopkins on HIV and hepatocellular carcinoma (HCC) in Uganda: The H2U Consortium. Hepatocellular carcinoma (HCC) is a very common and lethal cancer in Africa, and as patients with HIV live longer, the HCC burden will increase. The overarching goal of the Consortium is to reduce the heavy burden of HIV-associated HCC in sub-Saharan Africa. Building on long-standing collaborations, the Consortium expands will answer unresolved, high priority questions on the fundamental epidemiology and etiology of HIV-associated HCC, while expanding the clinical and laboratory research capacity in Uganda to address these issues. The Specific Aims include: 1) To enhance Ugandan investigator capacity for conducting high-level, collaborative, multidisciplinary scientific investigation of HV-associated HCC; 2) To solidify the clinical, population and translational research infrastructure; 3) To advance the foundational understanding of the epidemiology, mechanisms, and clinical spectrum of HIV-associated HCC; and 4)To inform prevention and treatment strategies applicable to HIV-associated HCC in resource-limited settings. We propose two major clinical projects, including a large case-control study of 600 HCC cases and 600 controls to define the role of HIV and related immunosuppression. We also will screen 3000 HIV-infected clinic patients for pre-malignant liver cirrhosis and for high-risk hepatitis B and aflatoxin-related biomarkers, then follow this high-risk group with regular HCC screening to determine feasibility and whether early stage HCC can be identified. Our Developmental Core will implement the H2U Scholars Award, pairing a Ugandan investigator with a senior Hopkins mentor and supporting career development and a collaborative pilot project. The proposed studies will enhance our clinical and mechanistic understanding of HIV-associated HCC, provide evidence on appropriate treatment, and inform intervention strategies to combat HIV and HCC in Africa. The impact of our integrated research and capacity development activities will be establishment of the H2U Consortium as a Center of Excellence on HIV and HCC in Africa.